Extending contact screening within a 50-m radius of an index tuberculosis patient using Xpert MTB/RIF in urban Pakistan: Did it impact treatment outcomes?

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Extending contact screening within a 50-m radius of an index tuberculosis patient using Xpert MTB/RIF in urban Pakistan:

Did it impact treatment outcomes?

Mahboob Ul Haq

^a,b,

*, Sven G. Hinderaker

^a

, Razia Fatima

^b

, Hemant Deepak Shewade

^c,d

, Einar Heldal

^e

, Abdullah Latif

^b

, Ajay M.V. Kumar

^c,d,f

aUniversityofBergen,Norway

bCommonManagementUnit(HIV/AIDS,TB&Malaria),Islamabad,Pakistan

cCentreforOperationalResearch,InternationalUnionAgainstTuberculosisandLungDisease(TheUnion),Paris,France

dTheUnionSouth-EastAsiaOfﬁce,NewDelhi,India

eNorwegianInstituteofPublicHealth,Oslo,Norway

fYenepoyaMedicalCollege,Yenepoya(deemedtobeUniversity),Mangaluru,India

ARTICLE INFO Articlehistory:

Received9November2020

Receivedinrevisedform20January2021 Accepted21January2021

Keywords:

Pulmonarytuberculosis Treatmentoutcomes Extendedcontactscreening Passivecaseﬁndings

Favorableandunfavorableoutcomes

ABSTRACT

Background:Pakistanimplementedinitiativestodetecttuberculosis(TB)patientsthroughextended contactscreening(ECS);itimprovedcasedetectionbuttreatmentoutcomesneedassessment.

Objectives:TocomparetreatmentoutcomesofpulmonaryTB(PTB)patientsdetectedbyECSwiththose detectedbyroutinepassivecaseﬁnding(PCF).

Methods:AcohortstudyusingsecondaryprogramdataconductedinLahore,FaisalabadandRawalpindi districtsandIslamabadin 2013–15.We usedlogbinomial regressionmodelsto assessifECSwas associatedwithunfavorabletreatmentoutcomes(death,loss-to-follow-up,failure,notevaluated)after adjustingforpotentialconfounders.

Results:We included79,431peoplewith PTB;4604(5.8%)weredetected by ECSwith4052(88%) bacteriologicallyconfirmed. Inall PTBpatientstheproportionwithunfavorableoutcomes wasnot significantlydifferentinECSgroup(9.6%)comparedtoPCF(9.9%),however,amongbacteriologically confirmedpatientsunfavorableoutcomesweresignificantlylowerinECS(9.9%)thanPCFgroup(11.6%, P=0.001).ECSwasassociatedwithalowerriskofunfavorableoutcomes(adjustedrelativerisk(aRR) 0.90;95%CI0.82–0.99)among‘allPTB’patientsandbacteriologicallyconfirmedPTBpatients(aRR0.91;

95%CI0.82–1.00).

Conclusion:InPTBpatientsdetectedbyECSthetreatmentoutcomeswerenotinferiortothosedetected byPCF.

ThisisanopenaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

Introduction

Pakistan has a high burden of tuberculosis (TB) with an estimated 5,70,000 incident TB patients and 42,000 deaths in 2019;only58%oftheestimatedpatientswerediagnosed,notiﬁed and started on treatment (World Health Organization, 2020a).

Therefore, complementing standard “passive” case ﬁnding withactivecaseﬁndinghasbeenstronglyencouraged(Hoetal., 2016; World Health Organization, 2013). A cluster-randomized

controlledtrial conducted in Vietnamin 2010–15 showed that household-contact investigation with standard passive case ﬁnding was more effective than standard passive case ﬁnding aloneforthedetectionofTBinahigh-prevalencesetting(Foxetal., 2018).

ContacttracingandscreeninginitiativesamongcontactsofTB patient,includinginurbanslums,haveshownanincreaseincase detectionandnotiﬁcationandthereforeanopportunitytoreduce diagnosticdelay(Dowdyetal.,2013;Fatimaetal.,2014;Lorent etal.,2014;Milleretal.,2010;WorldHealthOrganization,2012, 2011).

TheNationalTBcontrolprogram(NTP)ofPakistanachieved nationwidecoverageofTBservicesinthepublichealthsector by2005withtheDOTSstrategy(DirectlyObservedTreatment, Shortcourse)nowupdatedtothe“EndTBstrategy”(National

*Correspondingauthorat:DepartmentofGlobalPublicHealthandPrimaryCare, UniversityofBergen,Norway.

E-mailaddresses:[email protected],[email protected](M.UlHaq) .

https://doi.org/10.1016/j.ijid.2021.01.054

ContentslistsavailableatScienceDirect

International Journal of Infectious Diseases

j o u r n a l h o m ep a g e : w w w . e l s e v i e r . c o m / l o c a te / i j i d

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Tuberculosis Programme, 2019a). The majority of the case ﬁnding is through the public sector (National Tuberculosis Programme,2019b)wherepeoplewithpresumptiveTBcometo apublichealthfacilityandareinvestigatedforTB;thisiscalled

“passivecasefinding” (PCF)andthe initiativecomesfrom the patients.Oftensuchpatientsarereferredbytheprivatehealth sector where diagnostic services are not available. Other patients who do not visit the health facility despite having symptoms may be identified by “active case finding (ACF)”, wherethehealthsystemtriestoreachoutintothecommunity to identify and diagnose patients with TB (World Health Organization,2012).ACFisalsodoneinpopulationswithhigh prevalenceofundetectedTBorinmarginalizedandvulnerable populationswithpooraccesstohealthservices(WorldHealth Organization,2013).

Pakistan NTP implemented an innovative type of ACF, an

‘extendedcontactscreening’(ECS)strategy.Thisinvolvedcommu- nitycontactinvestigationbeyondtheroutinehouseholdcontacts:

allindividualsinhouseholdswithina50-mradiusfromthehome of an index smear-positive TB patient were asked about TB symptoms;iftheyhadsymptomstheywereinvestigated.TheECS strategyincreasedcaseﬁndingbyaround8%,whichismorethan expected from normal annual increases in routine TB control (Fatimaetal.,2016).

However, there has been no assessment on whether ECS affectedthetreatmentoutcomes.Asystematicreviewpublished in2013identiﬁedsimilartreatmentoutcomesamongACFandPCF- detectedpatients(Lönnrothetal.,2013);whilemorerecentpapers showACFtohavesimilar(Khaingetal.,2018;Shewadeetal.,2019) orworseoutcomes(Sengaietal.,2020;Singhetal.,2020).Wehave notfoundanystudyfromPakistancomparingtreatmentoutcomes bycasedetectionstrategy.

Therefore, our objective was to compare the treatment outcomesofTBpatientsdetectedbytheECSstrategywiththose detectedinroutinePCFinselecteddistrictsofPakistan.

Methods

Studydesign

Thiswasacohortstudyinvolvinganalysisofroutineprogram data.

Setting Generalsetting

Pakistan has a populationof over 200 million (WorldBank, 2018).The health system includesgovernment(public) institu- tions,parastatalhealthinstitutions(armedforces,SuiGas,WAPDA (Pakistan Water and Power Development Authority), Railways, FaujiFoundation),theprivatesector,civilsocietyandphilanthrop- icinstitutions.Theprivatesectoris largeandunregulated,with qualiﬁed and unqualiﬁed health service providers that deliver general curativeservicestoabout75%ofPakistan’spopulation;

nearly90% ofpatientswithTB initiallyseekcareintheprivate sector(Fatimaetal.,2017).

Publichealthcareisdeliveredthroughanetworkofprimary, secondaryandtertiarylevelhealthfacilities.Theprimaryhealth carefacilitiesinclude civildispensaries,basichealth units,rural health centers, mother-child healthcare centers, urban health units,andurbanhealthcenters.Thesecondarylevelhealthcare facilities comprise sub-district hospitals and district hospitals.

Tertiary level health care is provided through teaching and specializedhospitals.

TBbasicmanagementunits(BMUs)arelocatedatthedistrict and sub-district hospitals, the rural health centers, and some

basichealthunits.ABMUhasastaffed laboratorydoingsmear microscopy(afewfacilitiesalsodoXpertMTB/RIFassays)anda doctor/qualiﬁedmedicalstafftrainedtodiagnoseandinitiateTB treatment. TB treatment involves 6–8 months of treatment providedunderdailydirectobservationbyahealthcareprovider, acommunityvolunteerora familymember.TheBMUisalsoa facility where TB patients return for re-examinations and conﬁrmationof cure. The BMU maintains records in standard formatsandprovidesperiodicreportstothedistrictcoordinator, includingreportsontreatmentoutcome(WorldHealthOrgani- zation, 2020b). Sputum microscopy services, Xpert MTB/RIF testing and TB treatment are provided free of charge. During 2013–15, all the BMUs followed the algorithm in Figure 1 to diagnoseTB.

Allthepatientsinthisstudyweretreatedinlinewithnational TBguidelines(2013–15)andunderdirectobservationasisroutine forPCF.Newpatients(neverbeentreatedbeforeortreated<30 days) were treated with 6 months’ treatment regimen, which consisted of 2 months of HRZE (H-Isoniazid, R-Rifampicin Z-Pyrazinamide,E-Ethambutol)inintensivephaseand4months ofHRincontinuationphase.Previouslytreatedpatients(treated for>30daysinthepast)weretreatedwith8months’regimenthat consistedof2monthsHRZES(S-Streptomycin),1monthHRZEand 5 months of HRE. Patients who were diagnosed as having rifampicinresistancewerereferredtodrug-resistantTBsitesfor secondlinetreatment.HIV testingwas notroutinely offeredto patients(PCForECS).

Extendedcontactscreening

During 2013–15, ECS was implemented in 4 mainly urban districts:Lahore,Rawalpindi,FaisalabadandIslamabad.(Figure2).

Therewere98BMUsforthepopulationof18million.Morethan 80%ofthepopulationinthesedistrictslive inurbanareas.The average socio-economic status of people living in the project districtsisbetterthantheaverageofPakistanbecauseofbetter jobsandbusinessopportunities.However,halfofthepopulation liveinslumswithpoorsocio-economicconditions.

ThePakistanNTPhadaprojectfundedbyTB-REACHwaveIII, intendedtofacilitate detectionofmore TB cases(Fatimaet al., 2016).

All people staying within a 50-m radius (ascertained using geographic information system, GIS) from the households of knownTBpatientswerecontactedandscreenedforTBbytrained projectstaff.A50-mradiuswaschosenbasedonthedatafromthe electronicTBsurveillancesystemwhichrevealedthepresenceof many cases coming from the same family, same address, or neighboringareas;suggestinghighratesofgeographicalcluster- ing.The approximatenumber ofhouseholds in this radiuswas deemedfeasibletobecoveredunderclosecommunityscreening by theNTP. Mobile phonesenabled with ARC GIS (version10) softwarewereusedbyﬁeldworkerstoidentifyhouseholdswithin a 50-m radius of theindex case and collect data. Allavailable peoplepermanentlyresidingwithina50-mradiuswerecontacted.

The participants were informed about a TB patient in the neighborhood(50-mradius) butcarewas takennottodisclose thename.Measuresweretakentosafeguardtheconﬁdentialityof theindexpatient.Anypersonwithaproductivecoughformore than2weekswasdeﬁnedasa‘presumptiveTB’patient.Onespot sputumsamplewascollectedandtransportedtotheclosestBMU fordiagnostictesting.Thesamediagnosticalgorithmasmentioned in Figure 1 was followed except for theuse of Xpert MTB/RIF (if available) assayamong sputum smear microscopy negative presumptive TB. Patients bacteriologically positive for TB were contactedbytheprojectstaffandreferredtothenearestBMUfor registrationandtreatmentinitiation.AllpresumptiveTBpatients aged <15 years were referred to specialist pediatric care for

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diagnosisandmanagement.Peoplewhosesputumtestednegative on both microscopy and X-pert MTB/RIF were referred to the nearest BMU for follow-up according to national guidelines.

Patients identiﬁedby ECS were marked“TB REACH” in the TB register.

Studypopulation

WeincludedallpeoplewithpulmonaryTB(PTB)registeredand treatedatpublicorprivatefacilityengagedwiththeNTPinLahore, Rawalpindi,Faisalabad,andIslamabadbetweenJuly2013andJune Figure2. MapofPakistanshowingthe4selecteddistrictsforextendedcontactscreeningfortuberculosis(2013–15).

Figure1.AlgorithmusedbyPakistanNTPforassessingapatientwithpresumptivetuberculosisinroutine(PCF)program(2013–15).

TB=tuberculosis,sm+ve=Smearpositive,sm-ve=Smearnegative,FLD=FirstLineDrug,CXR=ChestX-ray,MTB=Mycobacteriumtuberculosis,RR=Rifampicinresistant, SLD=Secondlinedrug.

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2015.Theywereclassifiedbasedoncasedetectionstrategy,i.e., detectedbyPCForbyECS.ThecasesidentifiedthroughECSwere markedas“TBREACH”intheTBregistersatfacilitylevelandtheir registrationfortreatmentwasassuredbythefieldhealthofficers.

AllpatientswereconsideredasPCFunlessreferredbyTBREACH Wave III project ﬁeld health workers (through household and community-based contact screening). This was conﬁrmed by reviewing the projectrecords. Patients with known rifampicin resistanceandtreatedwithsecond-linedrugswerenotincluded.

Datavariablesandsources

Case-based datawas enteredfromfacility-basedTB registers intoMSExcel.Forqualityassurance,ourdatabasewascompared with aggregated data in the routine quarterly reports, and disparities were manually re-checked with the original TB registers.

Patient characteristicsincluded case detection strategy,age, gender, district, TB category, bacteriological conﬁrmation and diabetes mellitusstatus.Treatmentoutcomeswereclassiﬁedas favorable (treatment completed and cured) and unfavorable outcomes (treatment failure, lost to follow up, died or not evaluated)(Table1).

Analysisandstatistics

Comparison of demographic and clinical characteristics of patientsdetectedusingECSandPCFwasdoneusingχ²test.The caseﬁndingstrategy(ECSorPCF)wasourexposureofinterestand the treatment outcome (unfavorable or favorable) was our outcomeofinterest.Weusedlogbinomialregressionmodelsto assesstheassociationbetweenECSandunfavorableoutcomeafter adjusting for potential confounders, giving crude and adjusted relativerisk(95%CIs).

Results

Weincluded79431personswithPTBofwhom4604(5.8%)were detectedbyECS;oftheseatotalof4052(88%)werebacteriologically conﬁrmed, with a similar proportion in both household (3058/

3477=87.9%)andcommunitycontacts(994/1127=88.2%).Outof 4052 bacteriologically conﬁrmed patients, 3573 (88.2%) were positiveonsmearmicroscopyonly,172(4.2%)onXpertonly(of these 160were microscopynegative and12 hadnomicroscopy result)and307(7.6%)werepositiveonboth.Wedonothavesimilar informationforthePCFgroup.

ThebaselinecharacteristicsofthePTBpatientsdetectedbyECS byroutinePCFareshowninTable2.Themeanagewas36years andstandarddeviation18yearsforbothgroups.Thereweremore males (56.2%) in the ECS group than in the PCF group (49.6%, P <0.001). In the ECS group,bacteriological conﬁrmation was higher(88.0%)thaninPCFgroup(36.5%,P<0.001)andthehistory ofpreviousTBtreatmentwaslower(0.5%)comparedtothePCF group(6.4%,P<0.001).

We have depicted the treatment outcomes for all patients, bacteriologicalconfirmedPTB patients, and clinicallydiagnosed PTBpatients,andstratifiedbycasefindingstrategyinTable3.On crude analysis, the proportion withunfavorable outcomes was lowerintheECSgroupwhencomparedtoPCFinallthreegroups, butwassignificantlyloweramongbacteriologicallyconfirmedPTB intheECSgroup(9.9%)comparedtoPCF(11.6%;(P<0.05).Among all PTB patients, there was a higher contribution of cure to treatmentsuccessintheECSgroup(48.1%)whencomparedtoPCF (18%).The ECSpatientsidentifiedbyXpert(160)had outcomes similartothoseinTable3:cured86(54%),completed59(37%), died1(1%),losttofollow-up7(4%),notevaluated7(4%).

Among the bacteriologically conﬁrmed patients in the ECS group those detected in the index household had similar unfavorableoutcomes (85of 994;9%)tothose detected in the community(316of3058;10%)(P=0.06,datanotinthetables).In clinicallydiagnosedcases,thedifferenceinproportionswasalso notsigniﬁcant(7.2%householdvs8.9%community).

Lessthan5%ofpatientswereenrolledatprivatehospitalsin bothgroups,thesameprotocolwasfollowedforthesepatients, andnodifferencewasobserved.

Table4showstheassociationbetweenthecasefindingstrategy andunfavorableoutcomesafteradjustingforpotentialconfound- ers.ECSwasassociatedwithlowerunfavorableoutcomesforall PTB patients and this was statistically significant. A similar associationwasobservedin thebacteriologicallyconfirmedPTB patientgroupwithalowerriskofunfavorableoutcomes(adjusted relative risk 0.91; 95% CI 0.82–1.00) compared to routine case finding; this association was not statisticallysignificant in the clinicallydiagnosedPTBcohort.

Discussion

Inthislargestudyfrom4districtsofPakistan,wefoundthatthe treatmentoutcomesamong PTBpatientsdetected byECS were similar to those detected by PCF. While the ECS group was associatedwithamarginallylowerriskofunfavorableoutcomes amongbacteriologicallyconﬁrmedPTBpatients,thiswasnotthe caseamongclinicallydiagnosedpatients.

This study had several strengths. It was the ﬁrst study in Pakistan to evaluate the treatment outcomes of PTB patients

Table1

OperationaldeﬁnitionsofTBtreatmentoutcomesusedinPakistan’snationalTBprogram(2013-15).

Outcome Deﬁnition

Endoftreatment

Cured ApulmonaryTBpatientwithbacteriologicallyconﬁrmedTBatthebeginningoftreatmentwhowassmear-orculture-negativeinthelast monthoftreatmentandonatleastonepreviousoccasion.

Treatmentcompleted ATBpatientwhocompletedtreatmentwithoutevidenceoffailureBUTwithnorecordtoshowthatsputumsmearorcultureresultsinthe lastmonthoftreatmentandonatleastonepreviousoccasionwerenegative,eitherbecausetestswerenotdoneorbecauseresultsare unavailable.

Treatmentfailed ATBpatientwhosesputumsmearorcultureispositiveatmonth5orlaterduringtreatment.

Losttofollow-up ATBpatientwhodidnotstarttreatmentorwhosetreatmentwasinterruptedfortwoconsecutivemonthsormore.

Died ATBpatientwhodiesforanyreasonbeforestartingorduringthecourseoftreatment.

Notevaluated ATBpatientforwhomnotreatmentoutcomeisassigned.Thisincludespatients“transferredout”toanothertreatmentunitaswellas patientsforwhomthetreatmentoutcomeisunknowntothereportingunit.

Favorableoutcome Thesumofcuredandtreatmentcompleted

Unfavorableoutcome Alloutcomesotherthancuredandtreatmentcompleted TB–tuberculosis.

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Table2

Characteristicsofpatientswithpulmonarytuberculosisin4districtsofPakistandetectedbypassivecaseﬁndingandbyextendedcontactscreening^a,2013-15.

Extendedcontactscreening Passivecaseﬁnding pvalue*

n (%) n (%)

Total 4604 (100) 74,827 (100)

Demographiccharacteristics

Ageinyears 0.971

<15 391 (8.4) 6508 (8.7)

1544 2613 (56.8) 42,384 (56.6)

4564 1192 (25.9) 19,293 (25.8)

65 408 (8.9) 6642 (8.9)

Sex

Male 2587 (56.2) 37,144 (49.6) <0.001

Female 2017 (43.8) 37,683 (50.4)

District

Lahore 1994 (43.3) 33,375 (44.6) <0.001

Faisalabad 1619 (35.2) 19,611 (26.2)

Rawalpindi 899 (19.5) 19,551 (26.1)

Islamabad 92 (2.0) 2290 (3.1)

Clinicalcharacteristics Classiﬁcationbylaboratory

Bacteriologicallyconﬁrmed 4052 (88.0) 27,299 (36.5) <0.001

Clinicallydiagnosed 552 (12.0) 47,528 (63.5)

Typeofpatient

Newpatient 4579 (99.5) 70,090 (93.6) <0.001

Previouslytreated 25 (0.5) 4737 (6.4)

DiabetesMellitusstatus

Yes 192 (4.2) 3176 (4.2) 0.419

No 4412 (95.8) 71,651 (95.8)

*Chisquaretest.

aCommunityscreeningwithina50-mradiusofindexcaseinadditiontohouseholdscreening.

Table3

Comparisonoftreatmentoutcomesofpeoplewithpulmonarytuberculosisin4districtsofPakistandetectedbypassivecaseﬁndingvsextendedcontactscreening^a,2013–15.

Treatmentoutcomes Extendedcontactscreening Passivecaseﬁnding Pvalue*forunfavorable

outcome

n (%) n (%)

AllTB 4604 74,827

[N=79,431]

Favorable(F) 4163 (90.4) 67,421 (90.1)

Unfavorable(U) 441 (9.6) 7406 (9.9) 0.480

Cured(F) 2217 (48.1) 13,496 (18.0)

Treatmentcompleted(F) 1946 (42.3) 53,925 (72.1)

Treatmentfailed(U) 39 (0.9) 485 (0.6)

Died(U) 93 (2.0) 1183 (1.6)

Losttofollowup(U) 203 (4.4) 4185 (5.6)

Notevaluated(U) 106 (2.3) 1553 (2.1)

Bacteriologicallyconﬁrmed 4052 (100) 27,299 (100)

[N=31,351]

Favorable(F) 3651 (90.1) 24,126 (88.4)

Unfavorable(U) 401 (9.9) 3173 (11.6) 0.001

Cured(F) 2217 (54.7) 13,496 (49.5)

Treatmentfailed(U) 39 (0.9) 298 (1.1)

Died(U) 91 (2.3) 679 (2.5)

Notevaluated(U) 100 (2.5) 852 (3.1)

Clinicallydiagnosed[N=48,080] 552 (100) 47,528 (100)

Favorable(F) 512 (92.8) 43,295 (91.1)

Unfavorable(U) 40 (7.2) 4,233 (8.9) 0.173

Treatmentfailed(U) 0 (0) 187 (0.4)

Died(U) 2 (0.4) 504 (1.0)

Notevaluated(U) 6 (1.1) 701 (1.4)

*Chisquaretest.

aCommunityscreeningwithin50-mradiusofindexcaseinadditiontohouseholdscreening.

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detectedbytheECSstrategyandcomparewithroutinePCF.We hadalargesamplesizeofPTBpatientsenrolledfortreatmentin4 highlypopulatedurbandistrictswithslums.Thiswasthefirsttime that Xpert MTB/RIF assay was used to improve bacteriological confirmation among smear negative contactsin Pakistan. Also, datarelatedtocasenotificationofbothECSandPCFwereobtained from routine data recorded at NTP sites; findings therefore reflectedconditionsontheground.

Thestudyhadanumberoflimitations.Somepatientsdetected byECSmayhavebeenwronglycategorizedasPCFinTBregistersat thehealthfacility,butnotviceversa.Weseenoreasonwhythese fewwronglycategorizedpatientsshouldhavedifferentoutcomes, andhencebiasourresults.Byslightlyreducingthesamplesizeof thesmallestgroupitmightmarginallyreducethestatisticalpower.

We believe that there were other predictors of TB treatment outcomesinoursettingwhichcouldnotbeassessed,asthesewere notroutinelycapturedbytheNTPinthestudyperiod;examples could be severity of disease, socioeconomic status, nutritional status, and smoking.Therefore,residualconfounding cannotbe ruled out. The TB recording and reportingsystem had nodata related to patient HIV status. According to 2016 Integrated Biological Behavioral SurveillanceSurvey (IBBS)HIV prevalence inPakistanislow(0.12%)andlimitedtospecialriskgroups,suchas intravenousdrugusersandsexworkers.Ourstudyincludedonly thoseTBpatientswhowerestartedontreatment–thustheimpact ofpre-treatmentlosstofollow-uponoveralloutcomescouldnot beassessed.ItispossiblethattheECSandPCFgroupsmighthave experienceddifferentratesofpre-treatmentlossesandthismight haveinﬂuencedthetreatmentoutcomes.Thisisalimitationand weareunabletoquantifyitsimpactonoverallresults. Another limitationmightberelatedtothedifferencesinthewayXpertwas usedinthe2groups.Whileabout12%ofpatientsintheECSgroup received an Xpert test (and thus therifampicin resistance was excluded),wedonotknowwhatproportionofthepatientsinPCF grouphadreceivedXpertandhadrifampicinresistanceexcluded prior toﬁrst-line treatment. Thismight haveintroduceda bias makingthe2groupsdifferentandmighthaveimpactedoutcomes.

Our studysuggeststhatthetreatmentoutcomesamong PTB patientsintheECSgrouparenotinferiortothatofthePCFgroup.

The marginally better outcomes in bacteriologically confirmed patientsmaybeduetobetterfollow-upintheECSgroup(reflected by thelowerratesof patientsnot evaluatedforoutcomes) and possiblybetterexclusionofrifampicinresistance beforestarting treatment.Overall,wefeelthatthedifferencesaremarginaland thoughstatisticallysignificant(drivenbylargesamplesize),they arenotprogrammaticallysignificant.

Theremaybesomesort of Hawthorneeffect,where partic- ipantsinourECSgroupgot(perhapsmarginally)moreattention fromthehealthsystemfacilitatingbetterfollowupcomparedwith routineTBcontrol.Ourstudyresultsaresimilartorecentstudiesin India and Myanmar, which showed nodifference in treatment outcomes;inIndiatheproportionofunfavorableoutcomeswas 10.2%intheACFand12.5%inthePCFgroup(P=0.468),inMyanmar the proportions were respectively 12.4% and 14.6% with no signiﬁcant differences found between ACF and PCF (Khaing etal.,2018;Shewade etal.,2019).Asystematicreviewin 2013 alsofoundnodifferenceinthetreatmentoutcomesforbothgroups (Lönnrothetal.,2013).Incontrast,anotherstudyfromIndiafound worsetreatment outcomesinACFthanPCF(33%vs14%)(Singh etal.,2020).Thesestudieshadsmallersamplesizeanddidnotuse XpertMTB/RIFamongsmearnegativecontacts,aswedidinour study.

Conclusionandrecommendations

Inconclusion,wefoundthattreatmentoutcomesamongPTB patientsdetected byECSwerenotinferiortothose forpatients detectedbyPCF.Statistically,theECSgrouphadmarginallybetter outcomes among bacteriologically confirmed patients; but this was driven by large sample size and we do not think these differences are programmatically significant. These findings shouldencouragestakeholdersinPakistantosupportcasefinding projectsamong householdcontactsand communitycontactsto findandtreatmissedTBcases,tocomplementtheindispensable routinePCF.

Funding

TBREACHsecretariatofStopTBPartnershipfundedthemain project.Nospeciﬁcfundingwasobtainedfromanyorganization forthisstudy.Publicationfeeinaninternationaljournaliscovered bytheUniversityofBergen.

Conﬂictofinterest Nonedeclared.

Ethics

EthicsapprovalwasobtainedfromtheEthicsAdvisoryGroupof InternationalUnionAgainstTuberculosisandLungDisease,Paris, France(EAGnumber-58/16)andtheRegionalEthicsCommitteein Table4

Effectofextendedcontactscreening^conunfavorabletreatmentoutcomeswhencomparedtopassivecaseﬁndingamongpeoplewithpulmonaryTBin4selectdistricts, Pakistan2013-15.

PulmonaryTB Caseﬁndingstrategy Total Unfavorableoutcome RR (95%CI) aRR^a (95%CI)

N n (%)

AllTB

Extendedcontactscreening 4604 441 (9.6) 0.97 (0.88,1.06) 0.90 (0.82,0.99)^b

Passivecaseﬁnding 74,827 7406 (9.9) Ref

Bacteriologicallyconﬁrmed

Extendedcontactscreening 4052 401 (9.9) 0.85 (0.77,0.94) 0.91 (0.82,1.00)^b

Clinicallyconﬁrmed

Extendedcontactscreening 552 40 (7.3) 0.81 (0.60,1.10) 0.79 (0.59,1.07)

TB–Tuberculosis.

aLogbinomialregression,adjustedforpotentialconfounders(age,sex,district,previoustreatmentandclassiﬁcationbylaboratory),ageandgenderwereadjustedasthey areuniversalconfounders.Diabetesstatuswasnotassociatedwithoutcomeofinterestbutassociatedwiththeexposureofinterest(caseﬁndingandthereforenotapotential confounder.

bP<0.05.

cCommunityscreeningwithina50-mradiusofindexcaseinadditiontohouseholdscreening.

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Norway (REK-Vest 2018/57). Administrative approvals were obtainedfromtheNationalandProvincialTBProgram,Pakistan.

Asthisresearchinvolvedanalysisofsecondarydata,theneedfor writteninformedconsentwaswaivedbytheethicscommittees.

Acknowledgements

Wearethankfultotheﬁeldhealthworkersfortheireffortsand totheUniversityofBergen,Norwayforprovidingagoodacademic background,theTBREACHsecretariatofStopTBPartnershipfor fundingthemainprojectandtheProvincialTBControlPrograms Pakistan.Wehighlyacknowledgethecorporationandfacilitation ofNationalTBControlProgram,ProvincialTBProgramManagers, District TB Coordinators, Provincial Program Ofﬁcers and DOTs facilitatorsofPunjabandIslamabad.

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